SAH hydrolase has been an attractive target for antiviral drug design based on the observation that many viruses require 5′-capped, methylated structures on their mRNA for efficient translation of viral proteins. Yuan et al., Exp. Opin. Ther. Patents, 9: 1197–1206 (1999); Yuan et al., in Adv. Antiviral Drug Des. vol 2, pp. 41–88, De Clercq (ed)., JAI Press, Inc. London, UK (1996). Inhibition of SAH hydrolase results in inhibition of S-adenosyl-L-methionine (SAM)-dependent methylation reactions, including viral mRNA methylation, thus inhibiting viral replication (Scheme 1).
Scheme 1. Mechanism of Methylation Based Inhibition of Viral Replication
Numerous inhibitors of SAH hydrolase have been identified from naturally occurring compounds and synthetic compounds. Most potent inhibitors are irreversible inhibitors, which irreversibly inactivate SAH hydrolase in a time-dependent fashion. Studies have demonstrated that irreversible inhibitors only produce narrow therapeutic windows due to their severe cytotoxic effects (Wolfe and Borchardt, Journal of Medicinal Chemistry, 34:1521–1530 (1991)). Since SAH hydrolase is a ubiquitous cellular enzyme with a very slow turnover rate (t1/2 =24 hours in mouse liver), irreversible inhibitors can cause prolonged inhibition of the enzyme activity. For instance, it can take up to seven days for complete recovery of enzyme activity, which can lead to unwanted side effects. The severe cytotoxicity associated with irreversible inhibitors has been the major factor that has impaired the development of these inhibitors into clinically useful drugs. Because of the cytotoxicity associated with irreversible inhibitors, reversible inhibitors are preferred.
However, at present, there are no known reversible SAH hydrolase inhibitors that are potent enough to produce substantial inhibitory activity against the enzyme when tested in vivo. For example, the reversible inhibitor (S)-9-(2,3-dihydroxypropyl)adenine ((S)-DHPA), which has a Ki value of 3.5 μM against SAH hydrolase, lacks inhibitory potency. (Votruba and Holy, Coll. Czech. Chem. Commun., 45:3039 (1980)). Though (s)-DHPA was reported to be a reversible inhibitor of isolated AdoHcy hydrolase (Votruba and Holy, Coll. Czech. Chem. Commun., 45:3039 (1980)), it was also reported to be a irreversible inhibitor of intracellular AdoHcy hydrolase (Schanche et al., Molecular Pharmacology, 26:553–558 (1984)). Thus, existing reversible inhibitors are not clinically useful therapeutic agents, and there remains a need for SAH hydrolase inhibitors that exhibit potency without the undesired cytotoxic effects.